Parkinson's disease (PD) is a complex disorder with a heterogeneous etiology. In this proposal we will focus on Ashkenazi Jews (AJ), a genetically isolated population. Using a case-control design, we will search for genetic association by linkage disequilibrium with the assumption that a common founder mutation(s) has been transmitted to affected individuals with its associated haplotype. The objectives of this proposal are to identify disease SNPs, haplotypes and/or founder mutation(s) in the p-glucocerebrosidase (GBA) gene that are associated with Parkinson's disease in the AJ population and to explore phenotypic differences between PD cases with and without GBA mutations. We aim to do this by evaluating and collecting DNA from an additional 119 unrelated AJ individuals with Parkinson's disease and 188 AJ spouse controls to generate a total of 300 cases and 300 controls available for analysis. All Parkinson's disease cases and controls will undergo a full neurological examination and will be evaluated using the Unified Parkinson's disease rating scale and a Gaucher disease symptom severity index and neurological status questionnaire towards identifying phenotypic differences between PD cases with and without GBA mutations. Second, to generate a high resolution SNP map of the GBA gene, determine haplotypes and analyze frequencies between cases and controls and identify one or more disease haplotypes/SNPs in association with PD and or founder mutations. Significantly, recent studies suggest that mutations in the GBA gene may be associated with Parkinson's disease and the lysosomal/autophagic pathway has also been implicated in PD pathogenesis. [unreadable] [unreadable]